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Rheumatoid Arthritis (RA) is a prevalent autoimmune disease characterized by inflammation of peripheral joints. Patients can be subdivided by the presence or absence of Rheumatoid Factor and anti-citrullinated protein antibodies (ACPA) in their circulation. Inflammation of the joint tissue is associated with infiltration of leukocytes from the blood, which can result in generation of lymphoid structures composed of B and T cells. Previous studies have shown that both memory B cells and antibody-secreting plasma cells populate the rheumatic joint tissue when captured from established and often long-standing disease. However, it has remained unclear, whether these cells are autoreactive and whether the associated lymphoid structures are present at the site of inflammation already at the time of diagnosis. Here, we used an integrated single cell and spatial transcriptomic approach to study B and plasma cells in synovial tissue of ACPA- and ACPA+ RA patients at this early time point. We found evidence for T cell help to B cells and presence of memory B and plasma cell pools in ACPA- as well as in ACPA+ RA. Our results demonstrated common supportive microenvironments in both patient subgroups, clonal relationships between the memory B and plasma cell pools and autoreactivity within the plasma cell compartment. These findings challenge our understanding of the dynamics of local adaptive immune responses in the RA joint of ACPA- and ACPA+ patients at the time of diagnosis, with direct implications for B and T cell targeting therapies for both patient subgroups.One Sentence SummaryA B cell maturation and plasma cell maintenance niche is evident at onset of Rheumatoid arthritis in both ACPA- and ACPA+ patients.

Vaccine-induced antibodies that interfere with viral entry are the protective correlate of most existing prophylactic vaccines. However, for highly variable viruses such as HIV-1, the ability to elicit broadly neutralizing antibody responses through vaccination has proven to be extremely difficult. The major targets for HIV-1 neutralizing antibodies are the viral envelope glycoprotein trimers on the surface of the virus that mediate receptor binding and entry. HIV-1 has evolved many mechanisms on the surface of envelope glycoproteins to evade antibody-mediated neutralization, including the masking of conserved regions by glycan, quaternary protein interactions and the presence of immunodominant variable elements. The primary challenge in the development of an HIV-1 vaccine that elicits broadly neutralizing antibodies therefore lies in the design of suitable envelope glycoprotein immunogens that circumvent these barriers. Here, we describe neutralizing determinants on the viral envelope glycoproteins that are defined by their function in receptor binding or by rare neutralizing antibodies isolated from HIV-infected individuals. We also describe the nonvariable cellular receptors involved in the HIV-1 entry process, or other cellular proteins, and ongoing studies to determine if antibodies against these proteins have efficacy as therapeutic reagents or, in some cases, as vaccine targets to interfere with HIV-1 entry.

Background We recently reported that immunization with cleavagedefective soluble HIV-1 envelope glycoproteins (Env) trimers in monkeys, but not in rabbits, results in the elicitation of antibodies directed against the co-receptor binding site of gp120. This finding demonstrates that the high affinity interaction between Env and primate CD4 results in an alteration of Env immunogenicity. To further investigate the impact of Env-CD4 in vivo interactions during vaccination, we immunized rhesus macaques with wild type (wt) and CD4 binding defective Env trimers.

Background Broadly neutralizing antibodies (bNAbs) against HIV-1 are not efficiently elicited by vaccination despite considerable efforts. bNAb elicitation is likely limited both by current envelope glycoproteins (Env) immunogens, which are not sufficient mimics of the native Env spike complex, and by the lack of immunization regimens that promote optimal development and maturation of B cell responses. So far, analyses from protein immunization studies focus mainly on serological antibody responses and less on responses at the B cell level. Here, we characterize frequencies of antigen-specific antibody secreting cells (ASC) and memory B cells in the periphery and bone marrow of rhesus macaques immunized with soluble gp140 trimers. These analyses provide a foundation for the design of improved immunization protocols to elicit bNAbs against HIV-1.